Citation Knight J, Andrade M (2018) Genes and chromosomes 4: common genetic conditions. Nursing Times [online]; 114: 10,

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1 Genetics Keywords Nondisjunction/Aneuploidy/ Trisomy/Autosomal/Recessive Tis article as been double-blind peer reviewed In tis article... Definitions of nondisjunction and aneuploidy Clinical features of common genetic disorders Rules of ineritance of genetic disorders Genes and cromosomes 4: common genetic conditions Key points An aneuploidy is a deviation from te diploid number te most well-known is Down s syndrome Trisomies are disorders in wic an extra cromosome is present People wit Klinefelter s syndrome ave an extra X cromosome, but teir Y cromosome means tey ave a male penotype Turner s syndrome is te only survivable cromosomal disorder in wic an entire cromosome is missing Single-gene defects can cause ineritable genetic diseases suc as cystic fibrosis, albinism and Huntington s disease Autors Jon Knigt and Maria Andrade are bot senior lecturers in biomedical science at te College of Human Healt and Science, Swansea University. Abstract Genetic disease often leads to unviable embryos or babies wit very sort lifespans. However, tere are also survivable genetic diseases for example, Down s syndrome, Klinefelter s syndrome, cystic fibrosis and Huntington s disease. Genetic diseases can be broadly classified into tose affecting entire cromosomes (cromosomal disorders) and tose affecting single genes (single-gene defects). Tis article explores tese diseases, explains teir causes, describes teir clinical features and depicts teir rules of ineritance. It is te fourt and last in our series on genes and cromosomes. Citation Knigt J, Andrade M (2018) Genes and cromosomes 4: common genetic conditions. Nursing Times [online]; 114: 10, Given tat te uman genome comprises around 3 billion base pairs of deoxyribonucleic acid (DNA), it is not surprising tat errors in te genetic code (genetic mutations) sometimes occur. Many are associated wit genetic diseases and pass troug generations in a predictable manner. Tis fourt and final article in our series on genes and cromosomes looks at genetic diseases, from tose affecting entire cromosomes (cromosomal disorders) to tose affecting single genes (single-gene defects). Cromosomal disorders Normal cell division During cell division (weter mitosis or meiosis), DNA condenses into tin treadlike structures called cromosomes. Tis allows easier separation of genetic material between moter and daugter cells. Wit te exception of gametes (spermatozoa and ova), all nucleated uman cells contain 23 pairs of cromosomes, giving te diploid number of 46 (see part 2). Wit age, cells gradually sustain cumulative damage. To replace old cells, identical daugter cells are produced by mitosis (normal cell division). During tis process, te diploid number is rigorously maintained and all daugter cells receive a complement of DNA identical to tat of teir parent cells (see part 2). To form new gametes, te germinal cells of te ovaries and testes undergo meiosis, in wic te diploid number is alved to te aploid number of 23. Eac of te 23 pairs of cromosomes are pulled apart so tat eac spermatozoon and ovum receives 23 cromosomes. During fertilisation, wen a aploid spermatozoon penetrates a aploid ovum, te diploid number is restored. Meiosis also ensures tat eac offspring receives rougly alf teir genes from eac parent (see part 2). Nondisjunction and aneuploidy As te uman body ages, te separation of cromosome pairs during meiosis (te process of cell division in germinal cells) becomes less efficient. Tis can result in spermatozoa or ova receiving extra or 54

2 Fig 1. Clinical features of Klinefelter s syndrome and Turner s syndrome Tall stature Poor beard growt Sort stature Minor breast development Webbed neck Sield cest Female pubic air pattern Underdeveloped breasts and widely spaced nipples Testicular atropy Rudimentary ovaries Nevi (a) Klinefelter s syndrome (47 XXY) (b) Turner s syndrome (45 X) PETER LAMB fewer cromosomes for example, 24 or 22 instead of 23. Tis faulty separation of cromosomes, known as nondisjunction, can result in various cromosomal diseases (Gottlieb and Tegay, 2018). During fertilisation, a aploid spermatozoon (bearing 23 cromosomes) fuses wit a aploid oocyte (bearing 23 cromosomes), wic means te diploid number of 46 is restored in te resulting zygote (fertilised ovum). In nondisjunction, gametes may contain extra or missing cromosomes, so te resulting zygote will not ave te diploid number. Any deviation from te diploid number is called aneuploidy te most well-known is Down s syndrome. In Down s syndrome, nondisjunction usually occurs during oogenesis (ova formation), resulting in some ova aving two copies of cromosome 21 instead of one. During fertilisation, te spermatozoon brings its own paternal copy, so te zygote ends up wit tree copies of cromosome 21 ence te name trisomy 21 (see part 1). A variety of oter clinically significant aneuploidies occur as a result of nondisjunction. In many of tem, embryos are unviable and often spontaneously miscarried early in pregnancy (Jia et al, 2015). Trisomies Among te survivable aneuploidies, most are trisomies tat is, cromosomal disorders in wic an extra cromosome is present. Altoug it as been estimated tat 80-90% of trisomies occur as a result of nondisjunction during oogenesis (particularly in older moters), tere is growing evidence tat tey can also occur because of nondisjunction during te formation of spermatozoa (Si and Martin, 2000). Trisomies result in well-defined syndromes wit caracteristic pysical and psycological features. Patients usually require long-term medical care and interventions from nurses and oter specialised ealt professionals. Two of te more common aneuploidies besides Down s syndrome are Patau s syndrome and Edwards syndrome. Patau s syndrome. Patau s syndrome (trisomy 13) occurs in embryos tat ave received an extra copy of cromosome 13. It is seen in 1 in 5,000 to 1 in 10,000 live birts, and regarded as te most serious survivable trisomy as its clinical features are usually severe. Tese include: Microcepaly (incomplete brain development); Missing eyes; Displaced nose; Cleft palate; Ear malformations; Polydactyly (extra fingers and/or toes). Many babies born wit Patau syndrome do not survive more tan a few days and 90% will die witin te first year of life; some rare individuals survive into early adultood (Bit.ly/NHSPataus). Edwards syndrome. Edwards syndrome (trisomy 18), seen in around 1 in 5,000 live birts, occurs in embryos tat ave inerited an extra copy of cromosome 18. It is te second most common autosomal trisomy after Down s syndrome. (Te concept of autosomal disease is explained later in tis article.) A large number of affected embryos are spontaneously miscarried or stillborn (Cereda and 55

3 Carey, 2012). For babies born wit Edward s syndrome, te outlook is generally poor. Most die sortly after birt and only around 10% survive longer tan a year. Sometimes only an extra fragment of cromosome 18 is inerited: tese babies tend to ave less severe pysical abnormalities and can live longer (Bit.ly/NHSEdwards). All forms of Edwards syndrome display a range of clinical features including: Low birtweigt; Exompalos (born wit intestines outside te body); Microcepaly (small/abnormally formed ead); Small mout and lower jaw; Cleft palate; Heart defects; Kidney disease; Severe learning disabilities. Wit medical support, some individuals wit Edwards syndrome survive into early adultood. Sex cromosome disorders Gender is determined by te final 23rd pair of cromosomes (see part 1) and, in most people, sex cromosomes come in one of two combinations: XX female; XY male. Some cromosomal disorders affect te sex cromosomes. In terms of gender determination, te presence of a Y cromosome is of greatest significance, as anyone wit a Y cromosome will pysically appear to be male (tat is, ave a male penotype), irrespective of te number of X cromosomes tey possess. Klinefelter s syndrome. Klinefelter s syndrome (XXY) occurs in between 1 in 500 and 1 in 1,000 male live birts as a result of nondisjunction of te sex cromosomes during te formation of eiter spermatozoa or ova. Some ova of older moters may ave two copies of te X cromosome (XX) instead of only one. If suc an ovum is fertilised by a normal Y-bearing spermatozoon, te result is an individual carrying te sex cromosomes XXY. Nondisjunction during spermatogenesis can result in an abnormal spermatozoon tat as bot an X and a Y cromosome. If suc a spermatozoon fertilises a normal X-bearing ovum, te result is, again, an XXY individual. Te presence of a Y cromosome means tat all individuals wit Klinefelter s syndrome ave a male appearance; owever, tere is often some feminisation, togeter wit oter caracteristics of te syndrome (Fig 1a). According to Grot et al (2013), common clinical features of Klinefelter s syndrome include: Hypogonadism (reduced testicular mass); Reduced testosterone production; Reduced fertility; Reduced facial and body air; Weakened muscles; Osteoporosis; Tall stature; Gynecomastia (development of feminine breast tissue); Poor language and reading skills. Most people wit Klinefelter s syndrome lead full, productive lives and can fater cildren, albeit usually wit te elp of in vitro fertilisation. Turner s syndrome. Turner s syndrome (X) is te only survivable cromosomal disorder in wic an entire cromosome is missing. People wit Turner s syndrome ave 45 cromosomes instead of 46. As tey carry no Y cromosome, tey always ave a female pysical appearance (female penotype). As wit Klinefelter s syndrome, Turner s syndrome arises as a result of nondisjunction during te formation of ova or spermatozoa. If an ovum loses its X cromosome or a spermatozoon loses eiter its X or Y cromosome, tere will only be one X cromosome present after fertilisation. Turner s syndrome (Fig 1b) occurs in around 1 in 2,000 female live birts and affected individuals display clinical features suc as: Absence of mature ovaries (rudimentary ovarian tissue); Wide sield-like cest wit widely spaced nipples; Fig 2. Ineritance of cystic fibrosis Wen two carriers of a single recessive cystic fibrosis gene ave a cild, tere is a 1 in 4 risk tat te cild will inerit te two recessive genes and tus develop te disease Moter carrying one dominant and one recessive cystic fibrosis gene C c Infertility; Amenorroea (absence of a menstrual cycle); Lack of breast tissue; Patces of darkened skin (nevi); Sort stature; Small fingernails; Heart-valve problems; Aortic coarctation (narrowed aorta); Risk of aortic aneurysm and aortic dissection; Webbing of skin around te neck; Attention deficit yperactivity disorder. Altoug women wit Turner s syndrome generally lead ealty normal lives, te lack of ovarian tissue means tat most cannot become pregnant or carry a cild to term naturally. However, tey can become pregnant using eiter ova tat ave been arvested from teir rudimentary ovaries early in life or donated eggs. Hormonal terapy may be needed during pregnancy to ensure it progresses to term. Women wit Turner s syndrome need to undergo a variety of cardiovascular tests, bot before becoming pregnant and during pregnancy, because of teir increased risk of aortic dissection (Gravolt et al, 2017). Single-gene defects Structural genes encode for te syntesis of proteins, wile control genes regulate te activity of structural genes (see part 1 and part 3). Mutations to bot structural and control genes can result in defective genes. Tese are classified according to te cromosomes on wic tey are located tat is, teir locus. Single-gene defects cause many of te ineritable genetic conditions; for example, cystic fibrosis, albinism and Huntington s disease. Fater carrying one dominant and one recessive cystic fibrosis gene C CC Cc c Cc cc 56

4 Te first 22 pairs of cromosomes are te same in men and women; tese are called te autosomes. Te 23rd and last pair determines gender and its cromosomes are called te sex cromosomes (see part 1). As tere are 22 pairs of autosomes and only one pair of sex cromosomes, most gene defects appear in te autosomes; tey are terefore called autosomal genetic disorders. Disorders affecting te sex cromosomes, called sex-linked genetic disorders, are rarer. Autosomal recessive disorders Most autosomal gene disorders are called recessive. In tese diseases, two copies of te defective gene are present te presence of even one of te normal dominant genes would override, and tereby mask, te effects of a single recessive defective gene (in wic case te disease would not develop). As most single-gene defects are autosomal and recessive in nature, te resultant genetic diseases are described as autosomal recessive. In genetics, dominant genes are represented by capital letters and recessive genes by lower-case letters. Cystic fibrosis. Cystic fibrosis is a single-gene defect particularly common in Nortern- European races, were it affects around 1 in 2,000 to 1 in 3,000 newborn babies (Bit.ly/CisticFibrosisStats). Te cystic fibrosis gene is located on cromosome 7 (one of te autosomes) and is recessive in nature. Tere are tree possible combinations of te cystic fibrosis gene (tree genotypes): CC normal genotype (disease not present, te person carries two dominant genes); Cc carrier (te person carries one dominant and one recessive gene, so tey do not develop te disease but can pass it on to teir cildren); cc disease present (te person carries two recessive genes). It is estimated tat around 1 in 25 people are carriers of te recessive diseasecausing gene (Bit.ly/CysticFibrosisCauses). A Punnett square (simple grid used in nougts and crosses) sows tat, wen two carriers (Cc) ave a cild, tere is a 1 in 4 risk tat te cild will inerit te two recessive genes, tereby developing te disease (Fig 2). Tis 3:1 ratio is common in single-gene recessive diseases and is known as a Mendelian ratio (named after Gregor Mendel, wo first accurately described ineritance in plants in te 1800s). Fig 3. Ineritance of Huntington s disease (autosomal dominant disorder) If a person wo carries a single copy of te defective gene (H) as a cild wit a person wo carries te normal genotype (), tere is a 50% cance tat te cild will inerit te defective gene and terefore ave Huntington s disease Person wo carries one dominant defective gene (H) and terefore as Huntington s disease H People wit cystic fibrosis ave problems regulating te movement of water and electrolytes in certain tissues. Tis results in a build-up of tick, sticky mucus in te lungs, pancreatic ducts and gastrointestinal tract. Patients require frequent assessments in ospital, regular pysioterapy and medications to elp sift te mucus from inside te lungs. Static mucus in te lungs increases te risk of infection and, over time, irritates lung tissue, wic becomes scarred (fibrosis). Tis makes breating progressively more difficult. Lung fibrosis increasingly strains te rigt side of te eart, so many patients ave pulmonary ypertension and cor pulmonale (enlargement of te rigt side of te eart), wic increases teir risk of mortality (Hayes et al, 2014). In te gut, blocked pancreatic ducts and tickened mucus can impede digestion (particularly of fats), tereby reducing te absorption of nutrients (Smyt, 2005). Altoug te treatment of cystic fibrosis as improved, life expectancy is still relatively low (30-40 years) (Bit.ly/CysticFibrosisLifeExpectancy). Cystic fibrosis is one of te genetic disorders tat may be amenable to treatment and even cured by using emerging gene terapies, in wic viruses are genetically manipulated to deliver te ealty cystic fibrosis gene into cells, wit te aim of restoring normal function. Albinism. Albinism, anoter autosomal recessive genetic disease, affects 1 in 20,000 people. Albinos ave very little or no melanin in teir skin and eyes, wic gives tem a distinctive pale skin and pale blue, violet or pinkis eyes. As wit cystic fibrosis, tere are tree possible genotypes: Person wo carries te normal genotype () H H AA normal genotype (disease not present); Aa carrier; aa condition present. It is tougt tat around 1 in 100 people carry te defective recessive gene. Wen two carriers ave cildren, tere is a 1 in 4 risk tat te cild will ave albinism, giving te same classic 3:1 Mendelian ratio as in cystic fibrosis. As melanin plays an essential role in protecting te skin and eyes from armful ultraviolet (UV) ligt (see part 3), albinos are at greater risk of UV-induced skin and eye damage and skin malignancies suc as malignant melanoma (Yasumizu et al, 2015). Tey need to limit teir exposure to direct sunligt and protect teir eyes wit glasses or contact lenses tat block te entry of UV ligt. Autosomal dominant disorders: Huntington s disease Not all single-gene defects are recessive in nature. Huntington s disease, also known as Huntington s corea, is an autosomal dominant genetic disease. In autosomal dominant genetic disorders, one inerited copy of te defective gene is enoug for te disease to develop. In Huntington s disease, tree gene combinations are possible: HH disease present (in a person possessing two dominant defective genes) H disease present (in a person possessing one dominant defective gene) normal genotype, disease not present (no defective genes present) 57

5 For more articles on genetics, go to nursingtimes.net/genetics Fig 4. Ineritance of autosomal dominant BRCA gene mutation Normal gene Defective BRCA gene Affected fater Unaffected moter 1 in 400 and 1 in 800 people in te general population (NHS England, 2015). Like Huntington s disease, BRCA1 and BRCA2 mutations are dominant in nature, so a single inerited copy of te defective gene is enoug to significantly increase te risk of breast cancer (Fig 4). Te ineritance of defective BRCA1 or BRCA2 genes is also associated wit an increased risk of oter malignancies, including ovarian cancer and some forms of lympoma and leukaemia (Friedenson, 2007). NT PETER LAMB Affected son Unaffected daugter Unaffected son Affected daugter If a person wo carries a single copy of te defective gene (H) as a cild wit a person wo carries te normal genotype (), tere is a 50% cance tat te cild will inerit te defective gene and terefore ave Huntington s disease (Fig 3). Huntington s disease is a neurodegenerative disease tat usually manifests between te ages of 30 and 50 years; te defective gene is located on cromosome 4. It results in te production of an abnormal form of a protein called untingtin, wic progressively damages neural tissue owever, te exact mecanisms remain poorly understood (Sari, 2011). Patients present wit a range of neurological issues including: Poor coordination; Jerky, spasmodic and uncontrollable movements (corea) similar to tose seen in Parkinson s disease; Problems cewing and swallowing food; Gradual cange in cognition wit progression to dementia. In te UK, Huntington s disease affects around 6.68 in 100,000 people (Rawlins et al, 2016). On average, following te onset of symptoms, life expectancy is around 20 years. During tat time, patients will require increasing medical care from nurses and oter ealt professionals. Altoug tere is currently no cure, tere are many medications tat can elp relieve te symptoms of Huntington s disease. Sex-linked genetic disorders Wen faulty genes are located on eiter of te sex cromosomes (X or Y), te ensuing genetic disorders are described as sexlinked. Most sex-linked genetic diseases are associated wit te X cromosome. As females ave two copies (XX) and males only one (XY), males are more likely to be affected: unlike females, tey ave no cance of aving a ealty gene tat could compensate for te defective one. For tat reason, all X-linked genetic disorders suc as red-green colour blindness and aemopilia disproportionately affect males (VanPutte et al, 2017). More tan 200 genes are known to be located on te Y cromosome and are terefore, described as Y-linked. Many are associated wit male reproductive function for example, TSPY, a gene tat encodes for testes-specific protein. Daugters can never inerit any gene tat is Y-linked as, by definition, females cannot possess a Y cromosome. Gene mutations and breast cancer As well as risk factors suc as age, obesity, certain forms of ormone-replacement terapy, alcool consumption and smoking, several gene mutations also increase te risk of breast cancer. Two of te best understood are te BRCA1 and BRCA2 mutations. Te normal forms of BRCA1 and BRCA2 genes encode for proteins tat play an important role in repairing DNA damage. Mutations in tese genes result in te syntesis of abnormal proteins, wic are unable to effectively repair DNA. Tis increases te risk of breast cancer (Friedenson, 2007). BRCA1 and BRCA2 mutations are estimated to affect between References Cereda A, Carey JC (2012) Te trisomy 18 syndrome. Orpanet Journal of Rare Diseases; 7: 81. Friedenson B (2007) Te BRCA1/2 patway prevents ematologic cancers in addition to breast and ovarian cancers. BMC Cancer; 7: 152. Gottlieb SF, Tegay DH (2018) Genetics, Nondisjunction. Treasure Island, FL: StatPearls Publising. Gravolt CH et al (2017) Clinical practice guidelines for te care of girls and women wit Turner syndrome: proceedings from te 2016 Cincinnati International Turner Syndrome Meeting. European Journal of Endocrinology; 177: 3, G1-G70. Grot KA et al (2013) Clinical review: Klinefelter syndrome a clinical update. Journal of Clinical Endocrinology and Metabolism; 98: 1, Hayes D Jr et al (2014) Pulmonary ypertension in cystic fibrosis wit advanced lung disease. American Journal of Respiratory and Critical Care Medicine; 190: 8, Jia CW et al (2015) Aneuploidy in early miscarriage and its related factors. Cinese Medical Journal; 128: 20, NHS England (2015) Clinical Commissioning Policy: Genetic Testing for BRCA1 and BRCA2 Mutations. Bit.ly/NHSE_BCRAmutations Rawlins MD et al (2016) Te prevalence of Huntington s disease. Neuroepidemiology; 46: 2, Sari Y (2011) Huntington s disease: from mutant untingtin protein to neurotropic factor terapy. International Journal of Biomedical Science; 7: 2, Si Q, Martin RH (2000) Aneuploidy in uman sperm: a review of te frequency and distribution of aneuploidy, effects of donor age and lifestyle factors. Cytogenetics and Cell Genetics; 90: 3-4, Smyt RL (2005) Diagnosis and management of cystic fibrosis. Arcives of Disease in Cildood Education and Practice; 90: ep1 ep6. VanPutte CL et al (2017) Seeley s Anatomy and Pysiology. New York, NY: McGraw-Hill Education. Yasumizu M et al (2015) Malignant skin tumors in patients wit oculocutaneous albinism. Pigmentary Disorders; 2: 218. CLINICAL SERIES Genes and cromosomes Part 1: Basic principles of genetics July Bit.ly/NTGenes1 Part 2: Cell division and genetic diversity August Bit.ly/NTGenes2 Part 3: Genes, proteins and mutations September Bit.ly/NTGenes3 Part 4: Genetic anomalies and disorders October 58